The efficacy of brief intervention for drug use among primary care patients is not known. As a result, national professional organizations do not recommend universal screening. Yet a strong theoretical case can be made for such screening: drug use is common and associated with numerous health consequences, patients usually do not seek help, and screening and brief intervention has proven efficacy for other substance use (e.g., alcohol). Policy has advanced based on this case: large federal efforts to disseminate screening and brief intervention are underway, and reimbursement codes for insurers to compensate clinicians for these activities have been developed. The discrepancy between the science and these policy developments underscore the need to test brief intervention's efficacy among patients identified by screening. The objective of this study, the Assessing Screening Plus brief Intervention's Resulting Efficacy to stop drug use (the ASPIRE) Study, is to determine the efficacy of two models of brief intervention for decreasing drug use and consequences in primary care patients. In collaboration with a state project implementing screening and brief intervention as part of a federal program, we will screen patients in a large hospital-based primary care practice for drug use. We will then enroll 1,800 screen-positive subjects, randomly assign them to 1 of 3 groups, and follow them for 6 months. Subjects in one intervention group will be assigned to a standard brief intervention model, conducted by trained health promotion advocates as part of local implementation of a widely disseminated federal program. In another group, subjects will be assigned to an enhanced, more-intensive brief intervention model that includes a booster contact and is conducted by master's-level counselors trained and monitored intensively to perform motivational interviewing. The control group will receive information (i.e., a written list of local resources to help people using drugs) and, at the end of six months, standard brief intervention if they are still using drugs. Primary outcomes are abstinence from drug use and drug use consequences including HIV- risk behaviors at 6 months, and receipt of substance dependence treatment (among those with dependence). We will also compare costs and outcomes associated with each group. The main hypotheses are that 1) an enhanced brief intervention model will have greater efficacy than screening and resource information alone (control) for increasing drug abstinence, decreasing drug use consequences (including HIV-risk behaviors), and increasing receipt of treatment, 2) a standard brief intervention model will have greater efficacy than control for the same outcomes, and 3) an enhanced brief intervention will have greater efficacy than a standard brief intervention. We also hypothesize that the enhanced brief intervention will have higher implementation costs but lower net intervention costs (implementation, future healthcare, and crime costs) than the other groups. Results of this study -- efficacy and costs of brief intervention for drug use -- will be essential for making decisions about disseminating drug use screening and brief intervention in primary care settings. Public Health Relevance: Drug use is very costly, can cause much harm, and often goes untreated. Brief interventions offered in primary care settings could reach many people who use drugs. This proposed clinical trial will assess the effectiveness of these brief interventions and is thus relevant because if these brief interventions are proven effective, their dissemination could significantly decrease the national burden of drug use.